They received bad news Monday when the Court turned away challenges from Barber v. Bryant and Campaign for Southern Equality v. Bryant.
"This law that targeted LGBT people [and] privileged specific religious beliefs over others - that was a harm in and of itself", said Littrell.
The law was thought to be vulnerable to legal challenge since a landmark September judgment that recognised article 21 guaranteed a right to privacy.
"Unfortunately, the Supreme Court's decision today leaves LGBT people in MS in the crosshairs of hate and humiliation, delaying justice and equality", said Beth Littrell of Lambda Legal.
The Mississippi challenge falls within a broader category of cases that followed the Supreme Court's 2015 Obergefell decision, which announced a constitutional right to same-sex marriage. Opponents said it authorises discrimination against LGBT people in violation of the US Constitution's guarantees of equal protection under the law and the separation of church and state.
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Decisions in some of those cases are still pending.
Among other things, the measure lets businesses refuse to provide marriage-related services to same-sex couples and allows judges, magistrates and justices of the peace to refuse to perform same-sex weddings.
A federal district judge issued a preliminary injunction against the law in June 2017, an act which the U.S. Court of Appeals for the Fifth Circuit quickly reversed.
The United States Supreme Court declined to hear appeals on two lawsuits aimed at striking down a MS law that allows businesses to refuse to service same-sex weddings. The Texas ruling only concerned whether the lawsuit can move forward, and was not a decision on the merits of the controversy.
But gay rights groups promised to continue their efforts to get the law struck down. It said that it was the job of the parliament to decide on scrapping laws. The Masterpiece Cakeshop case is centered on whether a baker morally opposed to same-sex marriage can decline to make cakes for same-sex weddings.
Social conservatives celebrated the Supreme Court's allowing the law to stand, with Alliance Defending Freedom's Kevin Theriot stating on Monday that laws like HB 1523 "protect freedom and harm no one".